Pan-cancer characterization of the pyrimidine catabolic enzyme UPB1 identifies a tumor-suppressive prognostic biomarker in skin cutaneous melanoma.

Metabolic reprogramming of pyrimidine metabolism contributes to tumor progression; however, the oncological role of beta-ureidopropionase 1 (UPB1), the terminal enzyme in pyrimidine catabolism, remains poorly understood. This study aimed to characterize the expression profile, prognostic value, molecular alterations, immune associations, and functional significance of UPB1 across multiple cancer types, with focused validation in skin cutaneous melanoma (SKCM). UPB1 expression and its clinical relevance were evaluated using TCGA-based pan-cancer datasets and integrated bioinformatics platforms, including SangerBox, TIMER 2.0, GEPIA2, UALCAN, GSCA, cBioPortal, and LinkedOmics. Its functional effects were assessed in SK-MEL-2 and A375 melanoma cells using UPB1 overexpression, proliferation and migration assays, and Western blot analysis of epithelial-mesenchymal transition markers. UPB1 was significantly downregulated in multiple tumor types, including SKCM. Reduced UPB1 expression was associated with advanced clinicopathological features and poorer overall survival, disease-free survival, and progression-free interval in several malignancies. Genetic analyses revealed predominantly missense mutations, with the highest alteration frequency observed in SKCM, as well as tumor-specific differences in promoter methylation. UPB1 expression was positively associated with the infiltration of effector immune cells and the expression of key immunomodulatory molecules. In melanoma cells, UPB1 overexpression inhibited proliferation and migration and suppressed epithelial-mesenchymal transition, as evidenced by increased E-cadherin expression and decreased N-cadherin and vimentin expression. Collectively, these findings suggest that UPB1 functions as a tumor-suppressive factor linked to pyrimidine catabolism and may serve as a prognostic biomarker, particularly in SKCM.